IndividualsinfectedwithHepatitisCvirus(HCV)willeithercleartheirinfection(becomeHCV RNAnegative)ordeveloppersistentinfectionwithinthefirsttwoyearsofinfection.HIVinfection leadstoimmunedysfunctionandismanifestedindecreaseratesofspontaneouscontrolof HCVinfectioninHIV/HCVcoinfectedindividuals.Highlyactiveantiretroviraltherapies(HAART) effectivelysuppressHIVreplicationresultinginimmunereconstitutionwhichmayaffect spontaneouscontrolofHCVinfection.Afewcasereportsandourpreliminarydatademonstrate thatspontaneouscontrolofHCVinfectioncanoccurinHIV/HCVcoinfectedindividuals chroniciallyinfectedwithHCVforupto21yearsfollowingeffectiveHAART(HIVRNA>40 copies/ml).Thus,weproposetodeterminetheprobabilityofspontaneouscontrolofchronic HCVinfectionfollowingeffectiveHAARTandidentifyassociatedimmunecorrelates. Inourstudy,wewillinvestigateHAART-mediatedspontaneousHCVclearanceusingthree largeHIVcohorts:MulticenterAIDSCohortStudy,Women?sInteragencyHIVStudy,andAIDS LinkedtotheIntraVenousExperiencestudy.ComprehensiveHCVvirologicaltestingwillbe usedtoaccuratelyidentifyspontaneousclearanceevents.Weexpecttoobservespontaneous controlofHCVviremiainatleast15%ofHIV/HCVcoinfectedsubjectsfollowingeffective HAART.Pre-HAART,post-HAARTandpost-HCVclearancesamplesfromcase(Clearance) subjectsandtime-matchedspecimensfrommatchedcontrol(Chronic)subjectswillbeselected forfurtheranalysis.HostfactorswillbeassessedfortheirassociationwithHAART-mediated spontaneouscontrolofchronicHCVinfection.InAim2,HCV-specificTcellresponsesincase andcontrolPBMCspecimenswillbeassessedusingELISpotanalysis.Weexpectthatthe breadth(#ofpositivepeptidepools)andmagnitude(#ofspotformingcolonies)ofHCV-specific Tcellresponseswillbegreaterincasescomparedtocontrols.InAim3,HCV-specific neutralizingantibody(nAb)responseswillbemeasuredusingalibraryofHCVpseudoparticles. Weexpecttodemonstrateanincreasedbreadth(#ofHCVppneutralized)andmagnitude(titer) incasescomparedtocontrols. Withsuccessfulcompletionofthisstudywewillbegintounderstandimmuneprocessesthatare restoredbyHAARTandalsoimportantincontrolofHCVinfection.Identificationofimmune correlatesassociatedwithHAART-mediatedspontaneousHCVclearancewillleadtofurther clinicalandbasicscienceinvestigationsintoHIVsuppressionofHCVimmuneresponsesand mayhighlightpotentialtargetsfordevelopmentofanHCVvaccine.